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Mastering the FDAelectronicregistration processIt has been roughly 18 months since the FDA Structured Product Labeling (SPL) electronic registrationrequirement took effect. Ron Ball takes a look at what we have learned so far.

Since SPL electronic registration tookeffect, nearly all firms required to registerand list their products have, throughone means or another, navigated the

system. During this time we have assisted avariety of human and veterinary prescription,homeopathic, and over the counter drugmanufacturers to file their information withthe FDA. We have seen firsthand how theinformation submitted by medical gascompanies stacks up to the informationbeing submitted for other segments of thepharmaceutical industry, as well as how themedical gas industry is generally meeting FDArequirements for electronic drug product listings.This article will look at some of the common

pitfalls, and mistakes medical gas companieshave made with their facility registration anddrug product listings.

The transition from a paper registrationsystem to the new paperless process has notbeen without its problems. However, there isno denying that the new process is far superiorto what it replaced. Once you get used to thesystem you will find it much more user-friendly.For example, information updates that used totake months, now take days. We have literallysubmitted an information update for a companyone day, and seen the changed information onthe FDA's website the next business day.

More importantly, the new system nowfacilitates getting the information out of the

system and into users' hands. Under the oldpaper-based system, minimal detail submittedby a firm was available for viewing by anyoneoutside the FDA. By visiting various FDA webpages you could verify a firm's registrationstatus, if they had a National Drug Code (NDC)number on file, and what products and packagesizes they offered. This was about the sum totalof information that was available previously.Since the old paper process permitted thelisting of only a single package size - "variousper customer order" - many gas companiestook advantage of this option over the years.However, this meant there frequently was verylittle "real" information available from FDA's drugproduct listing website pages. ~

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~ When the new SPL process was introduced,by incorporating available web technologies intothe system, the agency introduced a remarkablenew method of viewing drug product listingssubmitted by firms. This new viewing process iscalled Daily Med, (http://dailymed.nlm.nih.gov/dailymed/about.cfm), and through it anyone withweb access can now see a firm's entire drugproduct listing, including copies of a firm's label.

The first thing you notice when viewing theon-line submissions is that some medical gasdrug product listings (DPL) compared to theDPL of more traditional drug products have theappearance of a real minimum effort job. It isalso not uncommon to find that many medicalgas DPL submissions do not even meet FDAminimum requirements. Since this informationis now widely available to everyone, includingyour potential customers, it only makes senseto invest the time required to make your drugproduct listing as professional as possible, inaddition to meeting minimum FDA requirements.

Common mistake #1 - missing labelinformationThe SPL process requires firms to enter into theform all of the information printed on the label,and then to also attach a digital image of thelabel to the file. By typing this information intothe SPL form it forms part of the code in theform's XML file. Once in the FDA's database thislabel information can easily be searched by theagency, which is something that could not easilybe accomplished under the old paper system.Label images are not searchable, and areincluded in the DPL to allow Daily Med usersto see a visual representation of the actuallabel on-line.

Unfortunately, a significant number of medicalgas DPLs do not have the label informationentered into the SPL form. They only containa copy of the label image. Firms, who havenot entered the label information into their SPLform, have not met the regulatory requirementfor drug product listing under the new electronicregistration process.

Common mistake #2 - wrong labelinformationUnlike more traditional pharmaceutical products,which all have unique label contents, theminimum language on medical gas labelsis standardized throughout the industry.The Compressed Gas Association's (CGA)publication C-7 Guide to the Preparationof Precautionary Labeling and Marking ofCompressed Gas Containers, provides thespecific language recommended by the gasindustry for medical gas cylinders. Since theFDA accepts the label language establishedthrough the CGA process, every medical gas

company can easily verify that their labels meetthe latest regulatory requirements by referencingthis document. With such an easy and publicallyavailable process, one would therefore assumeall medical gas labels would be in compliance.Sadly, this is not the case. We provide ourregistration customers a free label review, andthrough that process have found between 25and 30 percent of the labels we receive forreview need corrections to meet the latestrevision of CGA C-7, and around five percent ofthe labels were missing information required byFDA regulation. In one instance a firm was usingan industrial label as their medical label, thinkingthat these were the same. A notable percentageof the labels we reviewed also containedpunctuation and spelling mistakes.

this information is now widelyavailable to everyone, includingyour potential customers

Common mistake #3 - inadequately sizedlabel imageThe SPL process requires submitting an imageof each label with the drug product listing. TheFDA requires the label images to be a specificfile format and size. Through research and trialand error we have learned that the optimalimage resolution for most labels is between 75and 110 dpi. This gives for adequate clarity andimage readability, and still permits it to fit intothe SPL form. In reviewing Daily Med it appearsthat many firms used the typical scanner defaultof 300 dpi when entering their labels. Labelsscanned at this higher resolution typically takeup more than a page, and so often the entirelabel does not display in the SPL form. The FDAwants all labels to fit on a single page.

Common mistake #4 - black and white labelimagesMedical gas labels contain colored areasreferred to as diamonds. These colored areaspresent a graphic representation of the hazardclass of the gas. Black and white labelsinadequately convey this important informationto potential downstream users, so all medicalgas labels need to be inserted into SPL formsin color. Inserting a color image of a label isquick, simple, and easy - but unfortunatelymany companies did not take this easy but very

important step, and inserted black and whiteimages instead.

Common mistake #5 - unreadable labelimagesWhen inserting a label image into a SPL file, it isimportant that the label, when viewed on screenin the submission, can be read. Daily Med is fullof medical gas drug product listings that containlabel images that look like faxed copies offaxes. In these DPL the label information simplycannot be read on the screen. Once again, thisis not what the agency is looking for in terms oflabel image quality, as the FDA wants the labelinformation to be readable on screen. Whenyou view your firm's DPL in Daily Med, if thelabel image information cannot be read, youneed to update your information, and include ahigher-quality label image. We have found thatsometimes it is necessary to scan a label ata higher image rate, and then manipulate theimage to a different resolution for insertion.This typically preserves the readability of theimage, yet formats the image to the size that theFDA requires.

Common mistake #6 - wrong imagesubmittedIn the medical gas industry this mistake appearsto center around independent firms thatdeliver bulk products. In submitting their labelinformation some firms took a picture of the bulktrailer and inserted it as the label image. Theythen submitted the trailer placard information,DOT retest dates, and the trailer license platedata as the label information. These firmsapparently did not understand that the productCertificate of Analysis form, not the trailer licenseplate, is the correct drug product information tosubmit to the FDA. The Certificate of Analysis isthe document provided to the customer duringthe bulk delivery process, and is the correctinformation to use in the drug product listingof bulk medical gas products. The use of theCertificate of Analysis is consistent with otherbulk medical gas and Active PharmaceuticalIngredient (API) manufacturers, who submit thatinformation on their DPL.

Common mistake #7 - no drug productlisting submittedA small but significant number of medical gascompanies have submitted an electronic facilityregistration, but never submitted an electronicdrug product listing for their company. It appearsin some cases that the firm thought they didnot need to submit an electronic SPL, since theinformation was already on FDA's website fromthe paper process. In other instances somefirms found the complexity of the DPL form toodifficult for them to accomplish, and gave up the

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process without submitting a DPL. In both ofthese instances the firms need to complete andfile an electronic drug product listing with FDA tocomplete the SPL process.

Common mistake #8 - not all manufacturingsites listedFDA regulations require that independentmedical gas manufacturers and home careproviders also list their bulk product suppliers ontheir drug product listing. This means that thelocation or locations from which you receive yourbulk supplies of medical gases used to transfillinto cylinders or dewars/tanks needs to beentered as another manufacturing site on yourdrug product listing SPL. We usually mark thisinformation as confidential on the submissionswe prepare for our customers, so that thisinformation will not show up on Daily Med.

Correcting submission errorsJust because an SPL file successfully passedthe FDA validation routines does not mean itcomplies with all regulatory requirements forDrug Product Listings. At some point in theprocess a human reviewer will be involved.Currently the FDA is catching many of theabove noted errors when the DPL are originallysubmitted, but is aware that it missed somedue to the heavy volume of submissions overthe last year. Presently when a health carefacility complains to the agency regarding thepoor quality of a submission on Daily Med, theagency contacts the submitting firm, and asksit to make corrections. However, given thestandardization of medical gas Drug ProductListings vs. more traditional pharmaceuticals, itwill be a relatively easy exercise for the agencyto review the medical gas DPL on Daily Med,and firms with deficient submissions shouldexpect to be contacted by the agency with arequest to correct problems down the road.

We recommend that every firm should reviewtheir DPL on Daily Med, and if staff see someor all of the problems listed in this article in acompany's drug product listing, we encourageyou to act now and correct the information, andnot wait for FDA to contact you.

The re-registration processMany firms are now contemplating their secondforay into the FDA SPL system to process their2011 registration, and they face two potentialoptions. FDA provides a no change notificationSPL form that comes with the other SPL formsin the files you originally downloaded. Byproperly completing this form a firm can submita no change update to any existing form on filewith the agency. A key point to remember hereis that the Set ID # on the update form has tocorrespond to the Set ID # on the form

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©BOCCorrect cylinder labeling is essential, for FDArequirements and for your customers.

originally submitted.If the SPL information for your company has

changed since your last submission, then youwill need to revise and re-submit the sameform containing the updated information.Make sure you follow FDA's SPL form revisionprocedures exactly. Also don't forget to updateyour electronic certificate in you used a oneyear certificate initially. Once you get theupdated certificate, you will have to re-exportthe keys and send the public key to FDA. Ifyou forget don't get too concerned, the agencytypically sends a reminder email.

The new SPL process helps the FDA toprovide a new level of Drug Product Listinginformation to health care facilities and thepublic. Unlike in the past where most ofthis information was a matter of record onlybetween the submitting firm and the FDA,this information is now available globally via

o

the World Wide Web. Firms with carelesslyassembled, incorrect, or incomplete drugproduct listings will have that as part of theirpublic company image. In the highly competitivemedical gas market, a well- presented andcomplete drug product listing, and the companyimage it portrays, is likely to make thedifference with some customers when theychoose a supplier. IT...:.

Ron Ball

Formoreinformationon regulationsthat affectmedicalgasproducersandend-userscontact:RonBallatB&RComplianceAssociatesLLC+1 (317)297-8518; e-mail:ron.ball@brcompliance.com;go to: www.brcompliance.com

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